Estrogen plays a pivotal role in the proper development and physiological function of both female and male reproductive organ. Environmental chemicals that interfere with the estrogen functions could cause various cellular abnormalities, thus endanger our health. In order to address the question on how environmental factors interfere with estrogen?s function, we need to understand the intricate molecular event associated with gene expression under the influence of estrogen. With molecular approach, ER-mediated transactivation through the estrogen response element of lactoferrin gene has been studied. An estrogen-related receptor alpha (ERRa) binding element (ERRE) of the lactoferrin gene was found important in estrogen responsiveness. The ERRa modulates estrogen response either positively or negatively by competing for the same response element and coactivators of the ERs. Recently, evidence for ERRa regulation of genes involved in broad range of biological functions were presented. For example, ERRa regulates medium-chain acyl coenzyme A dehydrogenase (MCAD) in fatty acid metabolism, monoamine oxidase (MAOs) in neurotransmitter degradation, epithelial nitro oxide synthase (eNOS) in NO production in epithelial cells and sets of genes involve in mitochondria oxidative phosphorylation and mitochondria biogenesis during fasting. To understand the in vivo function of ERRa, generating ERRa-null or tissue specific ERRa-null mouse will be useful especially since the receptor is active without ligand. We have designed the construct to produce the floxed mouse and it is at the stage of identifying the recombinant chimera in ES cells. Since ERRa is constitutively active, regulation of its expression could be important in its biological roles. We found that estrogen stimulates ERRa gene expression in mouse uterus and a 34bp DNA element contains multiple steroid hormone response element half-sites (MHREs) of the gene is responsible for the estrogen stimulation. The MHREs also mediates the inducible peroxisome proliferators-activated receptor g coactivator-1a (PGC-1a) and estrogen related receptor g (ERRg) stimulation. These studies demonstrated a complicated regulation of ERRa gene expression through a common MHREs. Currently, we have map the nucleosome position of the ERRa gene at the MHREs region and we will examine the modification of the nucleosome at this region under different signaling pathways.